Doctors holding pill bottles

The statistics on opioid abuse in the United States is grim. In 2014, Opioids were responsible for 28,648 deaths according to the CDC. In fact, more people died of drug abuse that year than did of motor vehicle accidents. Worldwide the statistics are not any better; it is estimated that between 26.4 million and 38 million people abuse opioids.

The opioid prescription market has also grown significantly over the last two decades. Between 1995 and 2015 the number of prescriptions for opioids has escalated from 85 million to an estimated 220 million. With The United States being the largest global consumer with over 95% of hydrocodone and 80% of oxycodone products.

With these sobering statistics, the FDA recently initiated an all-encompassing action plan to combat opioid abuse amongst the American population.

As part of this initiative, the FDA is revising warnings and safety information for immediate-release (IR) opioid labeling. The goal of these new labeling requirements is to inform doctors better about the risks of opioids and how to prescribe these drugs safely.

Changes to the Opioid Labeling Regulation

New labeling requirements:

illustration with reviews

  • The addition of a BOXED WARNING to include information about Addiction, Abuse, and Misuse, Life Threatening Respiratory Depression, Accidental Ingestion, Neonatal Opioid Withdrawal Syndrome, and, as appropriate, significant drug product-specific interactions that would potentiate the opioid adverse effects.
  • Modifications to the INDICATIONS AND USAGE section that make clear that this class of drugs is to be reserved for management of pain severe enough to require an opioid analgesic and for which alternative treatment options (e.g., non-opioid analgesics or opioid combination products) are inadequate because they have not been or are not expected to be tolerated or have not provided or are not expected to provide adequate analgesia.
  • Modifications to the DOSAGE AND ADMINISTRATION section that include clearer instructions regarding patient monitoring, and drug administration, including initial dosage, dosage modifications, titration and maintenance of therapy, and discontinuation.
  • Modification of CONTRAINDICATIONS to include:
    • Significant respiratory depression
    • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment.
  • Addition to ADVERSE REACTIONS to include a list of serious adverse reactions described under WARNINGS AND PRECAUTIONS:
    • Addition of serotonin syndrome and adrenal insufficiency to the Postmarketing Experience subsection of ADVERSE REACTIONS
    • Addition of a statement about androgen deficiency to the Postmarketing Experience subsection of ADVERSE REACTIONS
  • Modification to WARNINGS AND PRECAUTIONS to include the following subsections:
    • Addiction, Abuse, and Misuse – Life-Threatening Respiratory Depression
    • Neonatal Opioid Withdrawal Syndrome
    • (if applicable) Significant drug product-specific interactions that would potentiate opioid effects
    • Risks Due to Interactions with Central Nervous System Depressants
    • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients
    • Adrenal Insufficiency
  • Modification to the DRUG INTERACTIONS section to include the following subsections:
    • Significant drug product-specific interactions that would potentiate opioid effects
    • Central Nervous System (CNS) Depressants
    • Serotonergic Drugs
  • Modification to the USE IN SPECIFIC POPULATIONS section to include specific information about NOWS and the potential for neonatal respiratory depression during delivery or with breastfeeding; the potential risk for infertility with chronic opioid use; and the greater risk of respiratory depression in the elderly.
  • Modification to the DRUG ABUSE AND DEPENDENCE section to include detailed information about abuse and dependence.
  • Modification to (or addition of) OVERDOSAGE section.
  • Addition of the following subsections to the PATIENT COUNSELING INFORMATION section:
    • Addiction, Abuse, and Misuse
    • Life-threatening Respiratory Depression
    • Accidental Ingestion
    • Interactions with Alcohol and Other CNS Depressants
    • Serotonin Syndrome
    • Adrenal Insufficiency
    • Pregnancy; Neonatal Opioid Withdrawal Syndrome, Embryo-Fetal Toxicity
    • Lactation
  • Addition of a MEDICATION GUIDE

Timeline for implementation of the new regulation

  • March 23 – FDA releases new labeling rule
  • April – Pharmaceutical companies have 30 days to submit a prior approval supplement (PAS), or notify FDA that you do not believe a labeling change is warranted
  • May – Sample labeling must be submitted to the FDA The sample labeling must follow the following format:
    • “Track Changes” WORD version of your proposed PI that tracks the addition of both proposed safety labeling changes Also track the deletion of approved labeling that results from the addition of the proposed safety labeling language and the adoption of the template.
    •  Annotated labeling, in table format, with a left column showing the approved language and a right column showing the disposition of that approved language
    • “Clean” version of label
  • December – Public talks close
  • January 2017 – New regulation takes effect

For pharmaceutical companies, their printers, and other suppliers, these new changes will require dramatic updates to their packaging materials including labels and product inserts. Given the short lead-time, companies will need to plan carefully. Consideration should be given to having the necessary tools in place to accelerate inspections while avoiding errors to ensure compliance.

For more information on the GlobalVision Quality Control Platform and how we can help with your compliance requirements, please visit, email: [email protected]

For more information on the FDA Opioids Action Plan, please visit: FDA

Learn More about FDA Data Integrity Guidelines